Abstract
BackgroundBoth DNA genotype and methylation of antisense non-coding RNA in the INK4 locus (ANRIL) have been robustly associated with coronary artery disease (CAD), but the interdependent mechanisms of genotype and methylation remain unclear.MethodsEighteen tag single nucleotide polymorphisms (SNPs) of ANRIL were genotyped in a matched case–control study (cases 503 and controls 503). DNA methylation of ANRIL and the INK4/ARF locus (p14ARF, p15INK4b and p16INK4a) was measured using pyrosequencing in the same set of samples (cases 100 and controls 100).ResultsPolymorphisms of ANRIL (rs1004638, rs1333048 and rs1333050) were significantly associated with CAD (p < 0.05). The incidence of CAD, multi-vessel disease, and modified Gensini scores demonstrated a strong, direct association with ANRIL gene dosage (p < 0.05). There was no significant association between ANRIL polymorphisms and myocardial infarction/acute coronary syndrome (MI/ACS) (p > 0.05). Methylation levels of ANRIL were similar between the two studied groups (p > 0.05), but were different in the rs1004638 genotype, with AA and AT genotype having a higher level of ANRIL methylation (pos4, p = 0.006; pos8, p = 0.019). Further Spearman analyses indicated that methylation levels of ANRIL were positively associated with systolic blood pressure (pos6, r = 0.248, p = 0.013), diastolic blood pressure (pos3, r = 0.213, p = 0.034; pos6, r = 0.220, p = 0.028), and triglyceride (pos4, r = 0.253, p = 0.013), and negatively associated with high-density lipoprotein cholesterol (pos2, r = − 0.243, p = 0.017). Additionally, we identified 12 transcription factor binding sites (TFBS) within the methylated ANRIL region, and functional annotation indicated these TFBS were associated with basal transcription. Methylation at the INK4/ARF locus was not associated with ANRIL genotype.ConclusionsThese results indicate that ANRIL genotype (tag SNPs rs1004638, rs1333048 and rs1333050) mainly affects coronary atherosclerosis, but not MI/ACS. There may be allele-related DNA methylation and allele-related binding of transcription factors within the ANRIL promoter.
Highlights
Both DNA genotype and methylation of antisense non-coding RNA in the INK4 locus (ANRIL) have been robustly associated with coronary artery disease (CAD), but the interdependent mechanisms of genotype and methylation remain unclear
We systematically examined the polymorphisms of ANRIL using haplotype tag Single nucleotide polymorphism (SNP) and detected their associations with CAD risk and the severity of coronary atherosclerosis, and explored the potential relationship between the polymorphism of ANRIL and DNA methylation of ANRIL and the INK4/ARF locus in a Chinese population
Homozygous carriers showed higher coronary atherosclerosis risk, whereas heterozygous carriers showed intermediate risk between that of wild-type and homozygous carriers, indicating a genetic dose effect, especially for premature CAD. (2) ANRIL polymorphism was significantly associated with CAD severity, but not myocardial infarction (MI)/acute coronary syndrome (ACS). (3) DNA methylation levels of ANRIL were not associated with CAD, but were associated with rs1004638 and CAD risk factors (SBP, Diastolic blood pressure (DBP), TG and high-density lipoprotein cholesterol (HDL)). (4) Twelve transcription factor binding sites (TFBS) were predicted within the ANRIL methylation region
Summary
Both DNA genotype and methylation of antisense non-coding RNA in the INK4 locus (ANRIL) have been robustly associated with coronary artery disease (CAD), but the interdependent mechanisms of genotype and methylation remain unclear. Current genome-wide association studies (GWAS) have added a considerable number of loci to serve as genetic markers of coronary artery disease (CAD) and myocardial infarction (MI)/acute coronary syndrome (ACS). Loci most frequently replicated in independently unbiased GWAS are at Chr9p21.3, Chr6p24.1, and Chr1p13.3. The causative gene for CAD at this locus is unknown. The CAD core risk region on 9p21.3 harbors no coding genes, but expresses the long non-coding RNA antisense non-coding RNA in the INK4 locus (ANRIL). The closest adjacent protein-coding genes are in the INK4/ARF locus, which encodes the key tumor
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